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Cited by 810T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisCytokine Signaling Pathways and Interactions

The DOI matches its Crossref record; 51 of the 55 references it cites were found in a registry or an index.

Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells

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Rincón, Mercedes, Anguita, Juan, Nakamura, Tetsuo, Fikrig, Erol, Flavell, Richard A.·1997·The Journal of Experimental Medicine
DOI 10.1084/jem.185.3.461PMC PMC2196041
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Abstract

Interleukin (IL)-4 is the most potent factor that causes naive CD4+ T cells to differentiate to the T helper cell (Th) 2 phenotype, while IL-12 and interferon γ trigger the differentiation of Th1 cells. However, the source of the initial polarizing IL-4 remains unclear. Here, we show that IL-6, probably secreted by antigen-presenting cells, is able to polarize naive CD4+ T cells to effector Th2 cells by inducing the initial production of IL-4 in CD4+ T cells. These results show that the nature of the cytokine (IL-12 or IL-6), which is produced by antigen-presenting cells in response to a particular pathogen, is a key factor in determining the nature of the immune response.

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Figure 1 IL-6 directs differentiation of CD4+ T cells into Th2 cells. (A) Total CD4+ T cells (106/ml) were purified from normal B10.BR mice and stimulated (in the presence of 5 × 105 cell/ml syngeneic APCs) with Con A (2.5 μg/ml) alone, Con A plus IL-4 (103 U/ml) or Con A plus IL-12 (3.5 ng/ml), in the absence (−) or presence of IL-6 (100 ng/ml) or IL-2 (50 U/ml). After 4 d, cells were exhaustively washed and restimulated (106 cells/ml) with Con A alone (2.5 μg/ml) in the absence of APCs or additional cytokines. Supernatants were harvested 24 h later and analyzed for IL-4 and IFN-γ production by ELISA. (B) Total CD4+ population was isolated from Cyt c TCR transgenic mice, and the naive CD4+ CD45RBhighCD44low subpopulation was purified by cell sorting. Naive CD4+ T cells were then stimulated with Con A alone, Con A plus IL-4, or Con A plus IL-12, and APCs, in the presence or absence of IL-6. After 4 d, cells were exhaustively washed and restimulated (106 cell/ ml) with Con A alone for 24 h before harvesting the supernatants for cytokine measurement. (C) Naive CD4+CD45RBhighCD44low CD4+ T cells isolated from Cyt c TCR transgenic mice were stimulated with Cyt c peptide and APCs, in the presence of medium, IL-6 (100 ng/ml), or IL-4, (103 U/ml). After 4 d, cells were exhaustively washed and restimulated (106 cell/ml) with Cyt c peptide and APCs for 24 h. (D) Total CD4+ T cells from normal B10.BR mice were stimulated with immobilized anti– CD3 mAb (5 μg/ml) and soluble anti–CD28 (1 μg/ml) in the presence of medium (−), IL-6 (100 ng/ml), or IL-4 (103 U/ml) and, after 4 d, they were restimulated with immobilized anti–CD3 mAb. (E) Total CD4+ T cells from normal B10.BR mice were stimulated with Con A and APCs in the presence of medium (−), IL-6 (100 ng/ml) (IL-6), or IL-6 (100 ng/ml) plus anti–IL-4 mAb (10 μg/ml) (IL-6 + anti–IL-4), for 4 d. Cells were then restimulated (106 cells/ml) with Con A alone as described in A.
Figure 1 IL-6 directs differentiation of CD4+ T cells into Th2 cells. (A) Total CD4+ T cells (106/ml) were purified from normal B10.BR mice and stimulated (in the presence of 5 × 105 cell/ml syngeneic APCs) with Con A (2.5 μg/ml) alone, Con A plus IL-4 (103 U/ml) or Con A plus IL-12 (3.5 ng/ml), in the absence (−) or presence of IL-6 (100 ng/ml) or IL-2 (50 U/ml). After 4 d, cells were exhaustively washed and restimulated (106 cells/ml) with Con A alone (2.5 μg/ml) in the absence of APCs or additional cytokines. Supernatants were harvested 24 h later and analyzed for IL-4 and IFN-γ production by ELISA. (B) Total CD4+ population was isolated from Cyt c TCR transgenic mice, and the naive CD4+ CD45RBhighCD44low subpopulation was purified by cell sorting. Naive CD4+ T cells were then stimulated with Con A alone, Con A plus IL-4, or Con A plus IL-12, and APCs, in the presence or absence of IL-6. After 4 d, cells were exhaustively washed and restimulated (106 cell/ ml) with Con A alone for 24 h before harvesting the supernatants for cytokine measurement. (C) Naive CD4+CD45RBhighCD44low CD4+ T cells isolated from Cyt c TCR transgenic mice were stimulated with Cyt c peptide and APCs, in the presence of medium, IL-6 (100 ng/ml), or IL-4, (103 U/ml). After 4 d, cells were exhaustively washed and restimulated (106 cell/ml) with Cyt c peptide and APCs for 24 h. (D) Total CD4+ T cells from normal B10.BR mice were stimulated with immobilized anti– CD3 mAb (5 μg/ml) and soluble anti–CD28 (1 μg/ml) in the presence of medium (−), IL-6 (100 ng/ml), or IL-4 (103 U/ml) and, after 4 d, they were restimulated with immobilized anti–CD3 mAb. (E) Total CD4+ T cells from normal B10.BR mice were stimulated with Con A and APCs in the presence of medium (−), IL-6 (100 ng/ml) (IL-6), or IL-6 (100 ng/ml) plus anti–IL-4 mAb (10 μg/ml) (IL-6 + anti–IL-4), for 4 d. Cells were then restimulated (106 cells/ml) with Con A alone as described in A.CC BY-NC-SA · PubMed Central
Figure 2 Regulation of IL-6 secretion by APCs during the differentiation of Th1 and Th2 CD4+ T cells. (A) Total CD4+ T cells (B10.BR) were stimulated with Con A (2.5 μg/ml) plus IL-4 (103 U/ml) or IL-12 (3.5 ng/ml) in the presence of APCs. Supernatants were harvested at different times of stimulation (day 2, 3, or 4) and IL-6 secretion was analyzed. (B) Total CD4+ T cells were stimulated as described in A, but in the presence of anti–IL-6Rα chain mAb (10 μg/ml). The arrow indicates the production of IL-6 after 4 d of stimulation with Con A and IL-4, in the absence of anti–IL6Rα mAb. (C) Expression of IL6Rα during the differentiation of Th1 and Th2 cells. CD4+ T cells unstimulated (day 0) or stimulated in the presence of APCs, with Con A plus IL-4 (Con A/IL-4) or IL-12 (Con A/ IL-12) for different periods of time (day 1, 2, or 4) were harvested, stained with anti-CD4 and anti–IL-6Rα mAbs, and analyzed by FACS®. Fluorescence profiles show the expression of IL-6Rα in the CD4+ population.
Figure 2 Regulation of IL-6 secretion by APCs during the differentiation of Th1 and Th2 CD4+ T cells. (A) Total CD4+ T cells (B10.BR) were stimulated with Con A (2.5 μg/ml) plus IL-4 (103 U/ml) or IL-12 (3.5 ng/ml) in the presence of APCs. Supernatants were harvested at different times of stimulation (day 2, 3, or 4) and IL-6 secretion was analyzed. (B) Total CD4+ T cells were stimulated as described in A, but in the presence of anti–IL-6Rα chain mAb (10 μg/ml). The arrow indicates the production of IL-6 after 4 d of stimulation with Con A and IL-4, in the absence of anti–IL6Rα mAb. (C) Expression of IL6Rα during the differentiation of Th1 and Th2 cells. CD4+ T cells unstimulated (day 0) or stimulated in the presence of APCs, with Con A plus IL-4 (Con A/IL-4) or IL-12 (Con A/ IL-12) for different periods of time (day 1, 2, or 4) were harvested, stained with anti-CD4 and anti–IL-6Rα mAbs, and analyzed by FACS®. Fluorescence profiles show the expression of IL-6Rα in the CD4+ population.CC BY-NC-SA · PubMed Central
Figure 3 IL-6–producing APCs are required for the differentiation of Th2 cells. (A) Total CD4+ T cells (106/ml) were isolated from WT mice and stimulated with Con A (2.5 μg/ml) alone in the presence of APCs (5 × 105 cells/ml) from WT (WT APC) or IL-6–deficient (IL-6− /− APC) mice. After 4 d, CD4+ T cells were washed and restimulated (106 cells/ml) with Con A in the absence of APCs, and supernatants were collected after 24 h. (B) Total CD4+ T cells were isolated from IL-6–deficient (IL-6− /−) mice and stimulated with Con A plus medium (−), neutralizing anti–IL-6 mAb (10 μg/ml) (anti–IL-6), IL-6 (100 ng/ml), IL-4 (103 U/ml), or both (IL-4 + IL-6), in the presence of APCs from WT (WT APC) or IL-6– deficient (IL-6− /−) mice. After 4 d, cells were washed and restimulated (106 cells/ml) with Con A alone for 24 h. Only in the case where all cells (both CD4 T cells and APCs) were from IL-6−/− mice did we observe a slightly lower recovery (70–80% of the recovery from other conditions) after 4 d of primary culture. Nevertheless, cell number was normalized (106 cells/ml) before restimulation. (C) Induction of IL-4 gene expression in CD4+ Th2 cells differentiated in the presence of IL-6. Naive CD4+ T cells (12) from Cyt c TCR transgenic mice were primary cultured with moth Cyt c peptide (5 μg/ml) and APCs in the absence (−) or the presence of IL-6 (100 ng/ml) or IL-4 (103 U/ml) for 4 d. Cells were then washed and stimulated with Cyt c peptide and APCs. After 20 h, 2 × 105 cells were harvested and used for the quantitation of IL-4 mRNA by competitive RT-PCR. (Top) The expression of IL-4 transcripts. (Bottom) The expression of DR transcripts. Small arrow, the competitor DNA.
Figure 3 IL-6–producing APCs are required for the differentiation of Th2 cells. (A) Total CD4+ T cells (106/ml) were isolated from WT mice and stimulated with Con A (2.5 μg/ml) alone in the presence of APCs (5 × 105 cells/ml) from WT (WT APC) or IL-6–deficient (IL-6− /− APC) mice. After 4 d, CD4+ T cells were washed and restimulated (106 cells/ml) with Con A in the absence of APCs, and supernatants were collected after 24 h. (B) Total CD4+ T cells were isolated from IL-6–deficient (IL-6− /−) mice and stimulated with Con A plus medium (−), neutralizing anti–IL-6 mAb (10 μg/ml) (anti–IL-6), IL-6 (100 ng/ml), IL-4 (103 U/ml), or both (IL-4 + IL-6), in the presence of APCs from WT (WT APC) or IL-6– deficient (IL-6− /−) mice. After 4 d, cells were washed and restimulated (106 cells/ml) with Con A alone for 24 h. Only in the case where all cells (both CD4 T cells and APCs) were from IL-6−/− mice did we observe a slightly lower recovery (70–80% of the recovery from other conditions) after 4 d of primary culture. Nevertheless, cell number was normalized (106 cells/ml) before restimulation. (C) Induction of IL-4 gene expression in CD4+ Th2 cells differentiated in the presence of IL-6. Naive CD4+ T cells (12) from Cyt c TCR transgenic mice were primary cultured with moth Cyt c peptide (5 μg/ml) and APCs in the absence (−) or the presence of IL-6 (100 ng/ml) or IL-4 (103 U/ml) for 4 d. Cells were then washed and stimulated with Cyt c peptide and APCs. After 20 h, 2 × 105 cells were harvested and used for the quantitation of IL-4 mRNA by competitive RT-PCR. (Top) The expression of IL-4 transcripts. (Bottom) The expression of DR transcripts. Small arrow, the competitor DNA.CC BY-NC-SA · PubMed Central
Figure 4 Schematic model for the differentiation of precursors Th cells (pTh) into effector Th1 and Th2 cells.
Figure 4 Schematic model for the differentiation of precursors Th cells (pTh) into effector Th1 and Th2 cells.CC BY-NC-SA · PubMed Central

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  1. Chomczynski, 1987, Single-step method of RNA extraction by acid guanidinium thiocyanate-phenolchloroform, Anal Biochem, 162, 156, 10.1016/0003-2697(87)90021-2 · DOI

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Metadata

Authors
Rincón, M., Anguita, J., Nakamura, T., Fikrig, E., & Flavell, R. A.
Affiliations
  • Howard Hughes Medical Institute (US)
  • From the *Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8011; ‡Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-9031; and §Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520-8011
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
1997-02-03
Volume
185
Issue
3
Pages
461-470
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.185.3.461
PMC
PMC2196041
OpenAlex
W2150763544
Cited by
810
References
55
Citations by year
2026: 3 · 2025: 11 · 2024: 14 · 2023: 18 · 2022: 20 · 2021: 23 · 2020: 23 · 2019: 19 · 2018: 19 · 2017: 15 · 2016: 18 · 2015: 16 · 2014: 30 · 2013: 9 · 2012: 25
FWCI
29.64
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p01ai030548-09)
  • National Cancer Institute (CA-65861, R01CA065861)
  • National Institute of Allergy and Infectious Diseases (1-P01-AI30548)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Keywords
interleukin-6, IL-4, CD4+ T cells, Th2 differentiation, Th1 differentiation, antigen-presenting cells, immune regulation
MeSH terms
Animals, Antigen-Presenting Cells, Cell Differentiation, Mice, Inbred C57BL, CD4-Positive T-Lymphocytes, Interleukin-4, Interleukin-6, Mice

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